Throughout this application various publications are referred to in parentheses. Full citations for these references may be found at the end of the specification. The disclosures of these publications are hereby incorporated by reference in their entirety into the subject application to more fully describe the art to which the subject invention pertains.
Patent ductus arterious (PDA) is a common problem causing significant morbidity and mortality in preterm infants. The ductus arteriosus is a blood vessel that connects the aorta and pulmonary artery and plays an important role in fetal life. In full term newborn infants, the ductus arteriosus constricts by 24 to 48 hours of life. However, in preterm infants, the ductus arteriosus often remains patent. Persistent patent ductus arteriosus is a common problem with rates of 40-55% encountered in preterm infants <29 weeks gestation (McNamara and Sehgal 2007). A PDA with a significant left to right shunting can lead to increased neonatal morbidity such as respiratory distress, cardiac failure, low blood pressure, and decreased peripheral organ perfusion, and leads to an increased incidence of intraventricular hemorrhage, necrotizing enterocolitis and chronic lung disease (Sehgal and McNamara 2012). The important aspect of assessment of a PDA is whether the degree of left to right shunting across the PDA is of hemodynamic significance and will therefore require treatment (Evans et al. 2012b). Assessment of the significance of the ductal flow is challenging. The amount of transductal flow between the descending aorta and the pulmonary artery is dependent not only on the ductal diameter but also on the difference between the systemic and pulmonary vascular resistance (McNamara and Sehgal 2007). The physiologic effects include increased systemic to pulmonary blood flow during systole and reversal of normal aortic flow during diastole called ductal steal. The combination of ductal steal and low diastolic pressure results in regional hypoperfusion (Noori 2010, Evans et al. 2012a). Diastolic ductal steal phenomenon is seen in hemodynamically significant patent ductus arteriosus (HSDA) and resolves after ductal closure (Evans et al. 2012a). Symptomatic shunting through a PDA has been associated with worse respiratory outcomes (Evans 1995).
The current clinical evaluations, electrocardiogram (ECG) and chest X-ray (CXR) findings, are neither accurate nor specific. Doppler echocardiography has proved to be better than clinical examination in grading PDAs (McNamara and Sehgal 2007). It is unlikely that optimum timing of therapeutic intervention may be predicted by postnatal age, as the determinants of a hemodynamically significant ductal shunt include transductal resistance and physiological modifiers. The difficulty in precisely separating the pathological ductus arteriosus from the innocent ductus arteriosus may be due to the lack of scientific evidence of benefit or causality (McNamara and Sehgal 2007, Sehgal and McNamara 2012). The ensuing effect is medical ambiguity and an unending dispute of whether these neonates have to be treated, the optimum timing of treatment and implications to when intervention is most effective. The nature of the confusion is thought to relate to limitations and/or delays in appraisal of ductal significance (Sehgal and McNamara 2012). Trials to date have focused on time, method and duration of intervention but not to scale the hemodynamic significance. The conventional guide by which ductal significance has been ascertained is transductal diameter but this might not imply significance in some situations.
Recent literature has questioned the beneficial effects of therapeutic intervention. The reasons for this apparent lack of effect may relate to a lack of relationship of a HSDA to neonatal outcomes due to inaccurate assignment of hemodynamic significance. Other than clinical parameters and echocardiographic evaluation, there are no other non-invasive clinical tools to help assess this common but difficult diagnostic entity from a therapeutic standpoint.
Echocardiographic evaluation has been considered the gold standard for diagnosis of a patent ductus arteriosus, but quantifying the size of ductal flow which leads to negative consequences remains a problem (McNamara and Sehgal 2007, Evans et al. 2012a). The decision to treat is based on echocardiographic documentation of a left to right transductal shunt with quantifiable hemodynamic effects leading to clinical instability. The current definition of HSDA is not adequate since it is entirely reliant on size (McNamara and Sehgal 2007). A transductal diameter of >1.5 mm has been proposed as significant since data from a small study with a sample size of 50 suggest that beyond this cut-off, end organ hypoperfusion occurs (Kluckow and Evans 1995, Evans 1995). This definition is incomplete because it does not take into consideration the maturational status of the patient and other biological factors that may account for unpredictability in clinical presentation. The lack of a uniform approach is a key hindrance towards better comprehension of the clinical effect of a patent ductus.
Description of the transductal flow pattern and direction are important in directing treatment decisions. However, flow indicators have a lower predictive value for therapeutic interventions because apart from ductal diameter, flow is dependent on the relative systemic and pulmonary vascular resistance which are highly variable in preterm infants with respiratory problems. In neonates with pulmonary hypertension, ductal flow is either pure right to left when pulmonary arterial pressure is suprasystemic or bidirectional (right to left during systole and left to right during diastole when it is equal to systemic arterial pressure). Prior studies have demonstrated the duct as closing/restrictive or unrestrictive and pulsatile according to pulse wave Doppler flow patterns. A HSDA will have a large left to right with pulsatile flow pattern and peak velocity at end systole. The peak velocity at the end diastole is usually very low. This implies that the relative pulmonary and aortic pressures are equal at the end of diastole. The peak systolic velocity is usually less than 1.5 m/s when the ductus is unrestrictive. As the ductus constricts, flow velocity increases as blood accelerates across a narrower vessel leading to a reduction in the peak systolic/diastolic ratio. Computing the volume of transductal flow would offer the most precise assessment of hemodynamic compromise. However, the calculation is not practical with conventional two dimensional techniques due to ductal tortuosity, changes in the transductal diameter across it course and the turbulent rather than laminar nature of flow.
Other echocardiographic parameters have been used to assess the amount of pulmonary blood flow. There are no direct measures of increased pulmonary blood flow; however, left heart size and flow are useful surrogate determinants of the magnitude of flow and its impact. The Left Atrial/Aorta (LA/AO) ratio has been used in several studies to evaluate the significance of ductal shunting. Evans and Iyer (1995) showed that a LA/AO ratio of >1.4 is suggestive of a HSDA. This ratio derived using M-mode imaging from a long axis approach is the most well recognized surrogate of ductal significance and was first described by Silverman et al. in 1974. Independently these markers have poor sensitivity and specificity, which may be related to a number of factors. These include patient related factors such as hydration, left ventricle performance or transatrial shunt and operator dependent factors, which may lead to over or underestimation of these single dimensional measurements (Evans et al. 2012a).
Newer echocardiographic assessment to determine a clinically significant PDA have been to profile the pulmonary artery flow pattern, left heart flow quantification, left ventricular output, LVO/SVC ratio and flow velocity in the LPA, all of which have been studied using small sample size (El Hajjar et al. 2005). Pulmonary artery flow is typically laminar and exclusively systolic with maximum velocity of about 1.5 m/s. The presence of HSDA leads to diastolic flow in the main and branch pulmonary arteries with a turbulent systolic pattern. The magnitude of diastolic flow in the main and left branch pulmonary artery correlates well with the magnitude of left to right shunt, but these studies do not address the clinical impact of this finding (Evans et al. 2012a,b). Quantification of pulmonary venous flow may provide the best measure of pulmonary overcirculation; however, accurate estimation of flow is challenging due to the tortuosity of the veins and variability of flow between the veins (Evans et al. 2012a).
Previous approaches for detection of PDA remain unsatisfactory. Vital signs and physical examination are neither sensitive nor specific for detection of PDA and echocardiography, although non-invasive, is disruptive to the patient, expensive, and only describes the status of the ductus at one point in time. This leaves the clinician with uncertainty about ductal shunting between echocardiograms.
Photoplethymography (PPG) is an easy and inexpensive optical technique that can be used to detect change in blood volume in the microvascular bed of tissue. It is frequently utilized to make non-invasive measurements at the skin surface. In photoplethysmography, the emitted light passes through the skin and is reflected, absorbed, and scattered by the tissue and blood (Sahni 2012). The amount of the modulated transmitted or reflected light that reaches the photodetector is measured, and the changes in the photodetector current are presumed to be due to blood volume changes underneath the probe. The systolic increase in the arterial blood pressure is accompanied by an increase in arterial blood volume resulting in reduced light transmission (Nitzan et al. 2009). These variations are electronically amplified and recorded as a voltage signal called the photoplethysmograph (Sahni 2012). The PPG waveform comprises a physiological waveform attributed to cardiac synchronous changes in the peripheral blood volume with each heart beat and is superimposed on a varying baseline with various lower frequency components such as respiration, sympathetic nervous system and thermoregulation. Changes in the pulse shape characteristics can yield valuable diagnostic information about the cardiovascular system. PPG has been experimentally used to assess the viscoelastic properties of blood vessels including the volume elastic modulus of finger arteries, which is the arterial pulse pressure related to PPG volume change at specific transmural pressures (Elgendi 2012, Allen 2007). PPG has been used to calculate pulse wave phases, and the difference between the right hand and left foot phases has been reported to correlate with PDA in a group of 56 subjects (Goudjil et al. 2014). Oishi et al. (1993) reported monitoring neonatal peripheral circulation by electrocardiogram-to-oximeter pulse velocity in three subjects with different clinical conditions.
The present invention addresses the need for improved methods and apparatus for detecting patent ductus arteriosus (PDA) and monitoring ductus closure in newborns using photoplethysmographic measurements.